Pathogen recognition and induction of innate immunity and inflammation against

$552,438U19FY2017AINIH

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Paper 33436917 Paper 32295632 Paper 31917957 Paper 31687902 Paper 31534040 Paper 31534033 Paper 31415679 Paper 31413072 Paper 31409781 Paper 31242236 Paper 31237466 Paper 31235953 Paper 31090472 Paper 31026414 Paper 31019057 Paper 30952515 Paper 30704498 Paper 30635240 Paper 30626670 Paper 30550976 Paper 30457675 Paper 30439342 Paper 30388054 Paper 30297339 Paper 30247157 Paper 30171843 Paper 30158602 Paper 30135445 Paper 30068264 Paper 30018145 Paper 29982912 Paper 29967348 Paper 29746837 Paper 29738748 Paper 29561519 Paper 29525521 Paper 29514902 Paper 29499768 Paper 29408905 Paper 29400709 Paper 29386359 Paper 29367469 Paper 29292385 Paper 29270173 Paper 29176765 Paper 29082104 Paper 28912382 Paper 28910635 Paper 28867493 Paper 28808965 Paper 28704657 Paper 28636958 Paper 28592649 Paper 28553952 Paper 28550425 Paper 28501330 Paper 28423319 Paper 28366204 Paper 28295214 Paper 28282568 Paper 28279563 Paper 28240606 Paper 28223406 Paper 28152048 Paper 28134626 Paper 28130493 Paper 28094802 Paper 28092376 Paper 28077630 Paper 27933528 Paper 27872814 Paper 27851926 Paper 27843766 Paper 27798603 Paper 27792906 Paper 27773535 Paper 27618651 Paper 27612415 Paper 27601663 Paper 27440901 Paper 27384652 Paper 27383988 Paper 27372014 Paper 27354515 Paper 27337340 Paper 27247001 Paper 27226371 Paper 27220616 Paper 27180225 Paper 27141421 Paper 27058872 Paper 27043414 Paper 26981429 Paper 26863439 Paper 26795869 Paper 26719279 Paper 26699642 Paper 26687364 Paper 26676770 Paper 26667390

Abstract

Project 1 is focused on understanding how Dengue virus (DENV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) are recognized by the host cell to trigger innate immune and inflammatory responses, and on defining how these cell-intrinsic and cell-extrinsic responses synergize to control infection. DENV, WNV, and JEV are genetically related flaviviruses and among the most important arthropod-borne viruses globally. These viruses are continually emerging and can cause severe hemorrhagic (DENV) or neurological disease (WNV and JEV) in humans. There is no approved antiviral therapeutic agent available for treatment of flavivirus infections. Moreover, there are no approved vaccines against DENV or WNV infection forthe billions of at-risk people, and the current JEV vaccines demonstrate limited durability of protection. Our preliminary studies indicate that susceptibility to flavivirus infection is controlled by innate immune/type I interferon (IFN) defenses triggered by pathogen-associated molecular pattern (PAMP) recognition of flavivirus RNA by RlG-l-like receptors (RLRs), RIG-I and MDA5. Additionally, we have identified a major role forthe Nod-like receptor protein (NLRP)3 in inflammasome signaling/IL-lbeta production in the virus-induced inflammatory response. These studies show that viral triggering of RLR and NLRP3 signaling pathways links innate immune and inflammatory responses to suppress flavivirus infection. The studies in this proposal will (1) Identify the viral PAMPs that trigger RLR signaling of innate immunity during DENV, WNV, and JEV infection; (2) Define the trigger(s) of NLRP3 activation and IL-1 D production by the neurotropic flaviviruses, WNV and JEV; and (3) Determine the molecular mechanisms of linkage and effector actions of innate immune/lFN responses and IL-lbeta inflammatory responses that control flavivirus infection

View original record on NIH RePORTER →